The completion of our genome scan on multiplex families with bipolar affective disorder provided evidence for susceptibility regions on 13q32, 1q32 and 18p11.2 and these findings were published recently [Detera-Wadleigh et al. (1999) Proc Natl Acad Sci USA 96:5604-5609]. Interestingly, these regions overlap with proposed chromosomal areas containing predisposing loci for schizophrenia. These findings raise the possibility that schizophrenia and affective disorders share some susceptibility loci. The long-term goal of the project is the identification of genes that contribute to overall genetic risk and the characterization of their biological function. It is anticipated that improvements in treatment, diagnosis and possibly, prevention will evolve once the genetic etiology of affective disorders and schizophrenia is established. Because the linkage regions are broad, the challenge to pinpoint susceptibility genes from among many positional candidate genes (genes localized in susceptibility regions) is formidable. The next objective therefore is to restrict the search for genes involved in predisposition within a narrow chromosomal segment. Three viable strategies are being employed: 1) association or linkage disequilibrium testing using closely-spaced polymorphisms on positional candidates, 2) physical mapping of the critical region, and 3) mutation screening of functionally-relevant genes that are encoded by the region. These strategies were used to further dissect the susceptibility region on 18p11.2. Previously, we cloned a second myo- inositol monophosphatase 2 (IMPA2) gene that qualifies as a functional candidate because the IMPA enzyme is inhibited by lithium, an effective medication for bipolar disorder. To permit detailed analysis of IMPA2 on patients the gene structure was determined and new single nucleotide polymorphisms (SNPs) were found (Yoshikawa et al., in press). An intron SNP displayed association with schizophrenia but not with affective disorder, and a SNP on the 5?UTR showed evidence for association with unipolar disorder but not with schizophrenia and bipolar disorder in Japanese samples (Yoshikawa et al., submitted). To validate these findings analysis of other independent patient collections must be conducted. Moreover, to establish that IMPA2 or a nearby gene is involved in conferring risk, the mutation or allele that could modify function or expression needs to be detected. - bipolar disorder, schizophrenia overlap, IMPA2 gene structure, IMPA2 association - Human Subjects